Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease

Arch Neurol. 1997 Apr;54(4):465-73. doi: 10.1001/archneur.1997.00550160091022.


Objective: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an m1 and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD).

Design: A 6-month, randomized, double-blind, placebo-controlled, parallel-group trial followed by a 1-month, single-blind, placebo washout.

Setting: Outpatients at 17 centers in the United States and Canada.

Participants: A total of 343 men and women at least 60 years of age with mild to moderate AD.

Interventions: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months.

Outcome measures: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER).

Results: A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P < or = .05), and CIBIC+ (high dose vs placebo; P < or = .02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P < or = .002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P < or = .02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group.

Conclusions: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / psychology
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / psychology
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Mental Disorders / drug therapy*
  • Mental Disorders / psychology
  • Middle Aged
  • Muscarinic Agonists / therapeutic use*
  • Placebos
  • Pyridines / therapeutic use*
  • Thiadiazoles / therapeutic use*


  • Muscarinic Agonists
  • Placebos
  • Pyridines
  • Thiadiazoles
  • xanomeline